Usher syndrome is a hereditary disorder that causes congenital hearing loss and retinitis pigmentosa. The three major clinical types, Usher syndrome type (USH1), type II (USH2) and type III of vestibular dysfunction. At least ten distinct genetic loci are now identified as being associated with the three clinical types of the disease. Of the ten Usher loci, two genes, USH1B and USH2A, have been identified. The USH1B encodes MYO7A, an unconventional myosin and USH2A encodes a putative extracellular matrix protein. What, if any, relation is there between these different classes of molecules and they relate to the other Usher genes' products. To address this question, we wish to identify additional Usher genes. We have the family resources to initiate such project. In the present proposal we wish to identify the Usher syndrome type 1A, type 2B and type 3 genes and their products. We will apply standard positional cloning strategy based on the construction of Sequence Tagged Site (STS) maps, integrated YAC/BAC/PAC contig maps and transcript maps for the respective critical regions. The Usher type 1A, 2B and 3 genes will be identified as genes carrying disease causing mutations in their coding or regulatory regions in the affected individuals. The identification of the various Usher genes not only provides an insight into a group of genes whose products play an important role in normal hearing, vision and vestibular function but establishes the possibility of gene based genetic diagnosis of the disease. It will provide insights into the development and the temporal and spatial organization of the inner ear and retina where the defect is believed to originate and will allow us to design therapies.